1. Field of the Invention
The present invention relates to novel compounds having inhibitory activity against the biosynthesis of triglycerides and inhibitory activity against the secretion of apolipoprotein B-containing lipoproteins, and pharmaceuticals comprising the compounds as an active component, especially prophylactic or therapeutic agents for hyperlipidemia.
2. Background Art
A change in dietary habits and an increase in population of persons of advanced age has lead to an increase in arteriosclerotic diseases. An abnormal increase in the level of cholesterol and triglycerides which are serum lipids (hyperlipidemia) may be one major risk factor of this group of diseases. For example, the proportion of patients suffering from familial combined hyperlipidemia (FCHL) among patients suffering from cardiac infarction is about 30%, which is a higher frequency than the case of other underlying diseases. Furthermore, the familial combined hyperlipidemia (FCHL) is known as an underlying disease which has a high risk of onset of ischemic hear diseases (Lipid, 2, 373 (1991)).
Hyperlipidemia, which takes place with high frequency as the complication of obesity and diabetes mellitus, is also recognized as a risk factor of arteriosclerosis (Diabetes, 37, 1595 (1988) and Int. J. Obesity, 15, 1 (1991)).
Further, it is also known that among hyperlipidemia, hypertriglyceridemia leads to pancreatitis and the like (Medical Practice, 12, 957 (1995)).
Therefore, the treatment of hyperlipidemia is important for the prevention and treatment of arteriosclerotic diseases, such as ischemic hear diseases and cerebrovascular diseases. Further, it has been pointed out that there is a possibility that hyperlipidemia attended with renal diseases evolves the renal disorder (Molecular Medicine, 31, 536 (1994)). For this reason, the necessity of treating hyperlipidemia has been proposed.
For the treatment or prevention of hyperlipidemia and arteriosclerotic diseases, statin compounds, such as Lovastatin, as agents for inhibiting the biosynthesis of cholesterol, particularly as agents for inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A reductase, and fibrate compounds, such as Bezafibrate, as agents for lowering the level of triglycerides, have been clinically used as pharmaceuticals.
Further, in recent years, reducing the level of triglycerides in serum and the level of apolipoprotein B-containing lipoprotein in serum, which is considered to induce arteriosclerosis, is expected to be useful for the prevention and treatment of the above diseases (Arterioscler. Thromb., 12, 1284 (1992) and Circulation, 85, 37 (1992)). One reason for this is that patients suffering from abetalipoproteinemia, in which apolipoprotein B-containing lipoprotein is not detected in blood, do not cause arteriosclerosis (Clin. Chem., 34, B9-12 (1988)).
Compounds known to have such activity include pyrrolecarboxylic acid derivatives, sulfonamide derivatives, phenylpiperazine derivatives, and biphenyl-2-carboxylic acid derivatives. Further, isoindolone derivatives having a substituent only in the nitrogen atom at the 2-position are also known (EP 643057 and WO 96/26205).
On the other hand, compounds having piperazine on the benzene ring in isoindolone and isoquinolone skeletons are known (WO 96/26187). These compounds, however, are different from the compounds of the present invention in the substituent of nitrogen at the 2-position and, in addition, acts as fibrinogen receptor antagonist. Thus, the above compounds are different from the compounds of the present invention in idea.
The present inventors have previously disclosed, in WO 98/54135, compounds which have piperazine on a benzene ring of isoindolone and isoquinolone skeletons and inhibit the secretion of apolipoprotain B-containing lipoprotein.
On the other hand, benzamide compounds are not known which have piperazine on a benzene ring and have two substituents other than a hydrogen atom on a nitrogen atom and, at the same time, inhibit the biosynthesis of triglycerides and inhibit the secretion of apolipoprotain B-containing lipoprotein.
Further, compounds having piperazine on a naphthyridinone skeleton are not also known. Furthermore, compounds are also not known which have piperazine on a pyridine skeleton and, in addition, have an N,N-di-substituted carbamoyl group.
Furthermore, compounds are not also known which have piperazine on naphthyridinone and pyridine skeletons and inhibit the secretion of apolipoprotein B-containing lipoproteins.
Agents, which have the activity of lowering serum triglyceride level and have the activity of lowering blood apolipoprotein B-containing lipoprotein level based on a new mechanism of action and, at the same time, do not cause, as side effect, the accumulation of some lipids within the liver which is found in abetalipoproteinemia, have been desired to be developed as prophylactic or therapeutic agents for hyperlipidemia or arteriosclerotic diseases (The Metabolic Basis of Inherited Disease, Sixth Edition, 1139 (1989)).
The present inventors disclose herein novel nitrogen-containing heterocyclic compounds, which have piperazine or piperidine on a benzene or pyridine ring of an isoindolone or isoquinolone skeleton and a skeleton similar to this skeleton, such as a quinazolinone, phthalazinone, or naphthyridinone skeleton, and further disclose benzamide compounds or amide-substituted pyridine compounds which have at least two substituents on a benzene or pyridine ring one of which is a substituent through piperazine or piperidine and another substituent is an amide having two substituents other than hydrogen atoms on the nitrogen atom. These compounds have high activity of lowering the blood triglyceride level and high activity of lowering the blood apolipoprotein B-containing lipoprotein level through high activity of lowering the blood lipid level, particularly inhibitory activity against the biosynthesis of triglycerides in the liver and inhibitory activity against the secretion of apolipoprotein B-containing lipoprotein from the liver, and are useful as therapeutic and prophylactic agents for hyperlipidemia and arteriosclerotic diseases.
Accordingly, an object of the present invention is to provide compounds which have inhibitory activity against the biosynthesis of triglycerides in the liver and, in addition, have inhibitory activity against the secretion of apolipoprotein B-containing lipoprotein from the liver, and are particularly excellent in inhibitory activity against the secretion of apolipoprotein B-containing lipoprotein, are free from the side effect of accumulation of the lipids within the liver. Thus, they are useful for the treatment and prevention of hyperlipidemia and arteriosclerotic diseases.
According to the present invention, there is provided a compound represented by formula (I) or a pharmacologically acceptable salt or solvate thereof: 
wherein
R1 and R2, which may be the same or different, represent
optionally substituted alkyl having 1 to 6 carbon atoms,
optionally substituted alkoxy having 1 to 6 carbon atoms,
optionally substituted cycloalkyl having 3 to 8 carbon atoms,
optionally substituted phenyl,
optionally substituted alkenyl having 2 to 6 carbon atoms,
optionally substituted alkynyl having 2 to 6 carbon atoms, or
an optionally substituted five- or six-membered saturated or unsaturated heterocyclic ring containing not more than 2 hetero-atoms, or
R1 and R2, together with a nitrogen atom to which R1 and R2 are attached, may form a five- or six-membered monocyclic ring which may further contain one hetero-atom or may be substituted or an eight- to ten-membered condensed ring which may further contain one hetero-atom or may be substituted;
R3 and R4, which may be the same or different, represent
a hydrogen atom,
optionally substituted alkyl having 1 to 6 carbon atoms,
a halogen atom,
hydroxyl,
nitrile,
alkoxycarbonyl having 2 to 5 carbon atoms,
alkoxy having 1 to 6 carbon atoms, or
carboxyl, or
R2 and R3 may be attached to each other to form group xe2x80x94(CH2)mxe2x80x94, wherein m is 1 or 2, xe2x80x94Nxe2x95x90CHxe2x80x94, xe2x80x94CHxe2x95x90Nxe2x80x94, or xe2x80x94(C1-6 alkyl)Cxe2x95x90Nxe2x80x94;
A, D, E, and G each represent a carbon atom, or any one of A, D, E, and G represents a nitrogen atom with the other three each representing a carbon atom,
Q represents a nitrogen atom or a carbon atom,
q, when Q represents a nitrogen atom, represents a single bond and, when Q represents a carbon atom, represents a single bond or a double bond;
Y represents a group represented by formula (II): 
xe2x80x83wherein
X represents a hydrogen atom; group xe2x80x94C(xe2x95x90O)N(R5)R6 wherein R5 and R6, which may be the same or different, represent a hydrogen atom, optionally substituted alkyl having 1 to 6 carbon atoms, optionally substituted cycloalkyl having 3 to 8 carbon atoms, optionally substituted phenyl, optionally substituted alkenyl having 2 to 6 carbon atoms, or optionally substituted alkynyl having 2 to 6 carbon atoms; or group xe2x80x94C(xe2x95x90O)OR7 wherein R7 represents a hydrogen atom or optionally substituted alkyl having 1 to 6 carbon atoms,
R8 is absent or represents a bond, an oxygen atom, a sulfur atom, xe2x80x94SO2xe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94CH2xe2x80x94CH2xe2x80x94, or xe2x80x94CHxe2x95x90CHxe2x80x94, and
R9 and R10, which may be the same or different, represent a hydrogen atom, optionally substituted alkyl having 1 to 6 carbon atoms, alkoxy having 1 to 6 carbon atoms, a halogen atom, or hydroxyl; and
Z represents xe2x80x94(CH2)nxe2x80x94, wherein n is an integer of 0 to 6, xe2x80x94Oxe2x80x94(CH2)ixe2x80x94, or xe2x80x94C(xe2x95x90O)NHxe2x80x94(CH2)ixe2x80x94 wherein i is an integer of 1 to 6, excluding the case where
R2 and R3 are attached to each other to form group (CH2)mxe2x80x94 wherein m is 1 or 2; A, D, E, and G each represent a carbon atom; Q represents a nitrogen atom; Y represents a group represented by formula (II) wherein X represents a hydrogen atom and R8 is absent; and Z represents xe2x80x94(CH2)nxe2x80x94.